Interleukin-9 (IL-9) is a pleiotrophic cytokine produced by activated T cells upon antigen stimulation and was first described in the mouse as a T-cell growth factor. IL-9 has a two subunit receptor that consists of IL-9Rα and the common γ chain, which is a shared component of the receptor complexes for IL-2, IL-4, IL-7, IL-13, IL-15 and possibly others.
A number of studies suggest that IL-9, as a mediator of Th2-dependent immune responses, may play a role in asthma. The IL-9 gene resides within the Th2 cytokine cluster on chromosome 5q. Linkage analysis shows an association between the IL-9 gene and elevated serum levels of IgE production and airway hyper-responsiveness. IL-9 transgenic mice exhibit many characteristics of human asthma: airway eosinophilia, elevated serum IgE and bronchial hyper-responsiveness. These transgenic mice have a strikingly robust peribronchial and perivascular eosinophilia after allergen challenge. The eosinophilia was shown to be coincident with the upregulation in lung epithelial cells of eotaxin, MIP-1 and MCP-1, -3, -5, which are chemotactic for eosinophils.
Expression of the IL-9 receptor on mature peripheral eosinophils has been demonstrated and IL-9 inhibits eosinophil apoptosis in a concentration dependent manner. It is also known that other cell types in the lung, i.e., alveolar macrophages and mast cells, when stimulated with IL-9 also produce chemokines. Other evidence for the role of IL-9 in asthma includes studies of the ability of IL-9 to stimulate mucin secretion by airway epithelial cells. The above studies taken together illustrate and support the role of IL-9 in regulating many clinical hallmarks of asthma and allergic inflammation.
Decreased IL-9 activity will have the beneficial effects of decreasing Th2 polarization of the T-cell response, decreasing eosinophil survival and neutrophil activity, and attenuating mucus production by airway epithelial cells. This will, in turn, reduce airway hyperreactivity and remodelling while increasing gas exchange and clearance, thus providing an effective therapeutic modality for several lung diseases including asthma, chronic obstructive pulmonary disease (emphysema and chronic bronchitis), and related pulmonary conditions.
IL-9 has also been shown to be a major anti-apoptotic factor for thymic lymphomas and may also contribute to the proliferation of other leukemias through its actions as an autocrine growth factor. Decreased IL-9 activity in patients with several types of leukemia will have the beneficial effect of slowing the cancerous growth and possibly enhancing the effects of other cancer therapies.
One method for attenuating IL-9-mediated activity is to inhibit cytokine signaling through its cognate cell-surface receptor. This can be achieved with bioengineered IL-9 antagonists. The engineered muteins would competitively inhibit the ability of wild-type IL-9 to signal by blocking its binding to the receptor.